Abstract Persistent pain following breast cancer surgery is increasingly recognized as an important clinical and public health issue due to the large number of women affected, the powerful negative impact that persistent pain has on emotional and physical functioning and its financial costs. Most of the more than a quarter of a million women newly diagnosed with breast cancer in the U.S. this year will undergo surgery as a part of curative treatment. The prevalence of persistent pain following surgical removal of the affected breast (mastectomy) or more limited surgeries (lumpectomy) is high, ranging from 25-60% across studies. Unlike acute post-operative pain, which is a normal response to surgical trauma, persistent pain at or near the surgical site has an uncertain multifaceted etiology, and no satisfactory pharmacological treatment. A critical question is whether key pain-related psychosocial factors are drivers of the continuing burden of persistent pain, and whether they could be ameliorated by non-pharmacological intervention. The research planned under this award will provide a first critical test of the hypothesized driving role of pain catastrophizing in persistent pain after breast cancer surgery. It also will explore the role of two other key psychosocial variables that may contribute to the burden associated with persistent pain after breast cancer surgery: self-efficacy for engaging in valued activities and psychological inflexibility. We have developed, manualized, and pilot tested a pain coping skills training intervention that specifically targets the needs of women with persistent pain following breast cancer surgery (Targeted PCST) and aims to reduce pain catastrophizing, increase self-efficacy for engaging in valued activities, and decrease psychological inflexibility. We propose a multiple-site, randomized clinical trial to evaluate the efficacy of the Targeted-PCST intervention. The study will be conducted in 9 diverse oncology clinics: 5 affiliated with Duke University/Duke Cancer Network and 4 affiliated with the University of Pittsburgh/UPMC Hillman Cancer Center. Participants (N=564) will be randomized to either receive: 1) Targeted-PCST, 2) a general health education intervention (control), or 3) usual care (control). Participants will complete assessments pre-intervention and at 3 months (post-intervention), 6 months follow-up, and 12 months follow-up. Study aims are: Aim1: Examine the impact of Targeted-PCST on persistent post-surgical pain severity and interference (i.e., PEG score), emotional distress (anxiety and depression), and cancer- specific distress. Aim 2: Investigate the impact of Targeted-PCST on pain catastrophizing, pain self-efficacy, and psychological inflexibility, and evaluate these variables as possible mediators of the benefits of Targeted- PCST. Aim 3: Evaluate the impact of Targeted-PCST on pain sensitivity and central sensitization, and explore whether changes in these variables mediate group differences in pain severity and interference.